Technical Appendix
Effectiveness and Cost of Quick Diagnostic Tests to
Determine Tetanus Immunity in Patients with a Wound in
French Emergency Departments
Dieynaba S. N’Diaye,
Michaël Schwarzinger,
Dorothée Obach,
Julien Poissy,
Sophie Matheron,
Enrique Casalino,
Yazdan Yazdanpanah.
INTRODUCTION
We assessed the effectiveness and cost of TQS use in French emergency departments (EDs) in
patients seeking care for a wound, compared with the medical interview regarding vaccination
history. We developed a decision-tree model that retraces clinical practice in the ED and includes
screening for immunity to tetanus in wounded patients, conditional prophylaxis administration,
and risk of tetanus occurrence.
Data used as input in the model were found through an extensive literature review. In this
Technical Appendix we describe in detail the sources of the probabilities and costs selected as
parameters. We explain the methods and provide the formula used to estimate the cohort life
expectancy and the patient’s tetanus immunity and its identification by the two diagnostic
1
methods compared. We also report in detail how we built incidence rates in non-protected
patients who were incorrectly diagnosed, according to their age and type of wound. Finally, we
present additional results of the sensitivity analyses conducted as part of this study.
METHODS
Input Data
Tetanus immunity
The true immunization rate of patients aged between 18 and 59 years was estimated based on
ELISA test results in the Colombet et al. study, which was conducted in a French multicenter
population of patients aged between 18 and 59 years old seeking medical attention for a wound in
French EDs [1]. The study reported a 94.6% seroprotection rate with a serum tetanus antitoxin
level above 0.1 IU/mL, which WHO guidelines consider protective [2]. Seroprevalence in
patients aged ≥65 years was estimated as 76.6% using data from a study of vaccination coverage
in this population by the French Institut de Veille Sanitaire. The probability of being up-to-date
with boosters was 71.2% for the French population between 18 and 64 years (less than 20 years
since the last booster) and 44.0% for those aged ≥65 years (less than 10 years since the last
booster). These values are from studies conducted by the French Institut de Veille Sanitaire [3, 4]
Patient screening
The probability of being identified as protected against tetanus or not, and positive and negative
predictive values were calculated based on the sensitivity and specificity of each diagnostic
method. Also determined were the probability of being up-to-date with booster shots for the
medical interview and seroprevalence for the TQS (formula shown Table A.1).
2
Tetanus incidence
Tetanus incidence was estimated based on age, the type of wound, and the administration or not
of unscheduled tetanus prophylaxis. Tetanus incidence rates were calculated by age group and
type of wound based on national observational data for 2000 to 2011.
Numerator
The number of tetanus cases was estimated by age based on mandatory disease notification data
published by the Institut de Veille Sanitaire between 2000 and 2011 [5-8]. These data indicated
an annual average of 3 cases in patients aged <70 years, and 14 cases in patients aged ≥70 years.
The estimated 64.5% exhaustiveness of reporting was included in our calculation [5-8].
Since our study population was ED patients, we focused only on tetanus cases involving an
emergency consultation. We assumed that only patients with acute open wounds came to the ED
(as opposed to those with chronic wounds or with an unidentified cutaneous portal of entry, who
are more likely to go to their general practitioners). Morbidity and Mortality Weekly Report
considers that 65.9% of tetanus cases are due to acute wounds, taking into account the fact that
not all patients with acute wounds present to the ED ([9]). According to the same American data,
only 36.5% of tetanus patients presenting with an acute open wound come to the ED ([9]. The
proportion of tetanus cases due to tetanus-prone wounds was estimated as 67.7% [5-8].
Denominator
Our study population was 1 658 000 adult patients, 16.6% of whom were used to calculate
specific incidence rates for patients aged ≥65 years, and 31% for tetanus-prone wounds [1, 1012].
Using the formula presented in Table A.2, we calculated specific tetanus incidence rates: for
patients between 18 and 64 years, 0.3 and 1.6 cases per million for non-tetanus-prone and
tetanus-prone wounds, respectively; and 8.8 and 41 cases per million for patients aged ≥65 years.
3
Outcomes
In patients in whom tetanus occurred, we considered that the probability of being hospitalized
was 1. Mortality and the probability of long-term sequelae were estimated using data on the
surveillance of tetanus from the Institut de Veille Sanitaire [5-8].
The cohort’s average life expectancy at entry in the model was calculated according to sex and
the average age of patients seeking care in French EDs (see formula Table A.1). It was based on
2011 data from the French National Institute of Statistics and Economic Studies and estimated as
40.9 and 9.1 years for patients aged between 18 and 64 and ≥65 years, respectively
(http://www.insee.fr/Population-data-2001). Life expectancy was at 0 when lethal tetanus case
occurred and remained the same if not.
Costs
Hospital costs related to tetanus cases were estimated using national hospitalization statistics
[13]. The diagnosis related group in which most of the tetanus cases were found was 18M104
corresponding to “Severe infectious diseases Level 4”. Its cost was modified by adjusting costs
related to the intensive care unit as if all tetanus cases were admitted to this unit. The average
period of time in intensive care was estimated as 42 days. The cost of the modified Diagnosis
Related Group was estimated as €209,000.
Costs associated with tetanus sequelae were assessed by taking into account stays in the followup care and rehabilitation departments, based on the diagnosis related group 40A22
“Rehabilitation of adult patients” for which the estimated average total period was 17 days [13].
The estimated cost of a one-day stay in these departments was €317, so the overall cost was
€5391 (=317 x 17 = 5391) per stay [13].
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Sensitivity analysis
Alternative scenarios
We also explored several scenarios in our sensitivity analysis. We considered another case where
a monovalent vaccine was administered (Vaccin Tétanique Pasteur®, €2.8), instead of the
tetravalent vaccine used in the base case (Revaxis®, €10). We also considered an alternative
where patients were treated with equine TIG (Immunoglobulines Équines Tétaniques Pasteur®,
€2.8) instead of human TIG in the base case (Gammatetanos®, €34.9) [14].
RESULTS
Alternative scenarios
We found that when patients were treated with equine TIG, the “TQS” strategy was no longer
cost-saving compared with “Medical Interview”. Similar results were observed when we
explored the case where a monovalent vaccine was administered. These results are shown in
Table A.3 (Effectiveness and cost of tetanus immunity diagnostic strategies in wounded patients
in French ED: scenario with a monovalent tetanus vaccine) and Table A.4. (Effectiveness and
cost of tetanus immunity diagnostic strategies in wounded patients in French ED: scenario with
an equine TIG)
5
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Colombet I, Saguez C, Sanson-Le Pors MJ, Coudert B, Chatellier G, Espinoza P:
Diagnosis of tetanus immunization status: multicenter assessment of a rapid
biological test. Clin Diagn Lab Immunol 2005, 12(9):1057-1062.
Borrow R, Balmer P, Roper M: The immunological basis for immunisation series.
Module 3: Tetanus Update 2006. © World Health Organization 2007, Department of
Immunization, Vaccines and Biologicals 2007(21 March 2011).
Gergely A, Bechet S, Goujon C, Pelicot M, Van Der Vliet D, Simons de Fanti A: La
couverture vaccinale contre le tétanos, la poliomyélite et la diphtérie en 2006 dans
une population âgée francilienne. Bull Epidémiol Hebd Saint-Maurice: Institut de veille
sanitaire 2008(9):61-64.
Guthmann JP, Fonteneau L, Antona A, Lévy-Bruhl D: La couverture vaccinale
diphtérie, tétanos, poliomyélite chez l'adulte en France : résultats de l'Enquête santé
et protection sociale, 2002. Bull Epidemiol Hebd Saint-Maurice: Institut de veille
sanitaire 2007, 51-52:441-445.
Antona D: Le tetanos en France entre 2000 et 2001. Bull Epidemiol Hebd SaintMaurice: Institut de veille sanitaire 2002, 40:197-199.
Antona D: Le tétanos en France en 2002-2004. Bull Epidemiol Hebd Saint-Maurice:
Institut de veille sanitaire 2006, 7:53-55.
Antona D: Le tétanos en France 2005 et 2007. Bull Epidemiol Hebd Saint-Maurice:
Institut de veille sanitaire 2008, 30-31:273-275.
Antona D: Le tétanos en france en 2008-2011 Bull Epidemiol Hebd Saint-Maurice:
Institut de veille sanitaire 2012(26: ):53-55.
Tetanus surveillance --- United States, 2001-2008. MMWR Morb Mortal Wkly Rep
2011, 60(12):365-369.
Stubbe M, Swinnen R, Crusiaux A, Mascart F, Lheureux PE: Seroprotection against
tetanus in patients attending an emergency department in Belgium and evaluation of
a bedside immunotest. Eur J Emerg Med 2007, 14(1):14-24.
Société Francophone de Médecine d’Urgence : SFMU: Prise en charge des plaies aux
urgences
In.:
http://www.sfmu.org/documents/consensus/cc_plaies_longue.pdf;
Copyright@SFMU 2005.
Directorate for Research, Studies, Evaluation and Statistics (DREES) annual
statistical survey on healthcare facilities from 2008 to 2012 [http://www.saediffusion.sante.gouv.fr/Collecte_2012/dwd_dwsgen3.aspx]
The Agency for Information on Hospital Care (ATIH) 2010 costs database
[http://www.atih.sante.fr/index.php?id=0009200003FF]
French Online Physicians’ Desk Reference database [http://www.vidal.fr/]
6
TABLES
7
Table A1 - Formula used in the model
Parameter
Life expectancy
Formula and base case value obtained
(Pr men in the cohort *Average male life expectancy of the age group) + ((1- Pr men in the cohort)
*Average female life expectancy of the age group)
18 to 64 years
40.9
≥65 years
9.1
(Medical interview sensitivity*Pr up-to-date with boosters)+((1-Medical interview specificity)*(1-Pr up-toPr of booster being assessed as up-to-date
date with boosters))
18 to 64 years
50.2%
≥65 years
39.0%
Pr positive TQS
(TQS sensitivity*Seroprevalence)+((1-TQS specificity )*(1-Seroprevalence))
18 to 64 years
65.7%
≥65 years
53.3%
Medical interview PPV
Pr up-to-date with boosters*Medical interview sensitivity/((Pr up-to-date with boosters*Medical interview
sensitivity)+((1-Pr up-to-date with boosters)*(1-Medical interview specificity)))
18 to 64 years
88.0%
≥65 years
69.9%
Medical interview NPV
(1-Pr up-to-date with boosters)*Medical interview specificity/(((1-Pr up-to-date with boosters)*Medical
interview specificity)
+ (Pr up-to-date with boosters*(1-Medical interview sensitivity)))
18 to 64 years
45.7%
≥65 years
72.6%
Seroprevalence*TQS sensitivity/((Seroprevalence*TQS sensitivity)+((1-Seroprevalence)*(1-TQS
TQS PPV
specificity )))
18 to 64 years
99.8%
≥65 years
99.1%
(1-Seroprevalence)*TQS specificity /(((1-Seroprevalence)*TQS specificity )+(Seroprevalence*(1-TQS
TQS NPV
sensitivity)))
18 to 64 years
15.3%
≥65 years
49.1%
Pr: probability; TQS: Tétanos Quick Stick; PPV: Positive predictive value; NPV: Negative predictive value
8
Table A.2- Model parameters used to calculate the tetanus rate incidence
Parameter
Cohort size (patients ≥18 years coming to French EDs
because of a wound)
Number of tetanus cases in France in 2000-2011
<70 years
≥70 years
Exhaustiveness of mandatory reporting of tetanus cases
Pr ED consultation for a wound│tetanus case
Pr tetanus-prone wound│tetanus case
Pr acute wound│tetanus case
Pr tetanus-prone wound│wound
Pr patients ≥65 years in the cohort
Tetanus incidence rates (per million)
Base case
value
Min
1,658,000
Max
Source
1,589,000 1,722,000 Calculus based on [11] and[12]
3
0
7
[5-8]
14
2
23
[5-8]
64.5%
60.0%
66.0%
[5-8]
36.5%
30.0%
40.0%
[9]
67.7%
53.6%
100%
[5-8]
65.9%
44.8%
73.1%
[5-8]
31.0%
18.1%
77.3%
[5-9]
16.6%
10.0%
20.0%
[10, 12],
(Annual number of tetanus case*Pr acute wound│tetanus *Pr type of
wound│tetanus*Pr ED consultation for a wound│tetanus) /(Exhaustivity of tetanus
declaration*Cohort size*Pr of patient of the age group))
18 to 64 years
Non-tetanus-prone wound
0.3
Tetanus-prone wound
1.6
≥65 years
Non-tetanus-prone wound
8.8
Tetanus-prone wound
41.0
Pr: probability; │: among (in case of a conditional probabilities); ED: Emergency department
9
Table A.3 - Scenario with a monovalent tetanus vaccine a
Cohort
Strategies
Tetanus
case
Life Years
(LY)
Strategy
Cost
TQS
Cost
Prophylaxis
Cost
Vaccine
dose
Medical
0.41
58,658,086.4 € 14,167,000
€ 14,081,000
1,033,000
Interview
N = 1,658,000
TQS
0.02
58,658,087.4 € 15,060,000 € 6,866,000
€ 8,189,000
601,000
∆
-0.39
1.0
€ 893,000 € 6,866,000
-€ 5,892,000
-432,000
ED: Emergency departments; LY: Life years; TQS: Tétanos Quick Sticks; TIG: Human tetanus immunoglobulins; N: Cohort size
a
Effectiveness and cost of tetanus immunity diagnostic strategies in wounded adult patients presenting to French EDs in 2012.
∆= Defined as the delta of the transition from the Medical Interview strategy to the TQS strategy
All wounded patients
TIG
dose
320,000
186,000
-134,000
Table A.4 - Scenario with an equine TIG a
Cohort
Strategies
Tetanus
case
Life Years
(LY)
Strategy
Cost
TQS
Cost
Prophylaxis
Cost
Vaccine
dose
Medical
0.41
58,658,086.4 € 11,721,000
€ 11,635,000
1,033,000
Interview
N = 1,658,000
TQS
0.02
58,658,087.4 € 13,637,000 € 6,866,000
€ 6,766,000
601,000
∆
-0.39
1.0
€ 1,916,000 € 6,866,000
-€ 4,869,000
-432,000
ED: Emergency departments; LY: Life years; TQS: Tétanos Quick Sticks; TIG: Human tetanus immunoglobulins; N: Cohort size
a
Effectiveness and cost of tetanus immunity diagnostic strategies in wounded adult patients presenting to French EDs in 2012.
∆= Defined as the delta of the transition from the Medical Interview strategy to the TQS strategy
All wounded patients
10
TIG
dose
320,000
186,000
-134,000